Unusual linkage patterns of ligands and their cognate receptors indicate a novel reason for non-random gene order in the human genome

Table 5 Evidence for or against dosage sensitivity of ligand and receptors that were possibly the source for or the consequence of block duplication

Gene	Evidence for dose sensitivity	References
HGF	Over-expression in retinal pigment epithelium induces retinal detachment	[58]
MET*	Autosomal dominant Hereditary papillary renal carcinoma is associated with mutations in MET	[59]
MST1	None: mouse knockout is without strong phenotype	[60]
RON	Hemizygous mice (Ron +/-) are highly susceptible to endotoxic shock and are compromised in their ability to downregulate nitric oxide production	[61]
DLL1	No report of heterozygous null phenotype nor of overexpression phentype
NOTCH3*	Autosomal dominant disorder CADASIL owing to mutation in NOTCH3	[62]
DLL3	None: the gene is associated with disease (SCDO1/2) in mutant homozygotes but no report of heterozygote phenotype.
NOTCH4	Upregulation of NOTCH4 is associated with mammary tumours	See OMIM 164951
FGF1	None: no phenotype in Fgf1 homozygous knockouts	[63]
FGFR3*	Autosomal dominant disorder ACH associated with mutation in FGFR3	See OMIM 134934
FGF2	Over-expression promotes bone growth	[64]
FGFR4	None: knockout homozygotes have no obvious phenotype	[65]
FGF8	Over-expression is associated with carcinogenesis	[66]
FGFR1*	Autosomal dominant Pfeiffer syndrome is owing to mutations in FGFR1	[67]
FGF17	None: heterozygote knockout has no phenotype	[68]
FGFR2*	Numerous autosomal dominant disorders associated with FGFR2	See OMIM 176943
FGF18	Dose sensitive liver and small intestine development	[69]

*Note: These five genes are known to be associated with human autosomal dominant disorders. Searching OMIM [70] for mapped genes with "autosomal dominant" somewhere in the title or the text and not "recessive" in the title, reveals an estimate of 1166 mapped genes which may be associated with autosomal dominant disorders. Assuming 22470 autosomal genes (as in the NC files) we should then have expected from a random sample of 17 autosomal genes less than one dominant, significantly less than observed (Chi-squared, P < 0.0001). However, in some cases the dominance is owing to negative mutations rather than dose per se.

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